DNA-scaffolded biomaterials enable modular and tunable control of - - PowerPoint PPT Presentation

DNA-scaffolded biomaterials enable modular and tunable control of immune cell therapies

Xiao Huang, PhD Postdoc Scholar, Desai Lab University of California San Francisco

The 16th US-Korea Forum

• n Nanotechnology

CAR-T therapy – revolutionary cancer therapy

CANCER CELL

T CELL

CD19 CAR

Brown & Mackall. Nature Reviews Immunology, 2019

Lim & June. Cell, 2017

Efficacy and safety are critical aspects for cancer therapy

On-tumor efficacy Off-tumor safety

Biomaterials can modulate immune cell behaviors

TUMOR EFFICACY Regulatory signals

P

SAFETY TUMOR

ON

NORMAL

Riley, et al. Nature Reviews Drug Discovery, 2019

Immune cell engaging particles (ICEp)

ATGCGCTACATGCTCTC

DNA scaffolds on biomaterials allows efficient loading and precise control of functional proteins

Unmatch Match

RT 2 mins

FAST

R strand : G strand : B strand Input 3:1:1 Input 1:1:1 Input 1:1:3

5𝛎m

VERSATILE EFFICIENT

5 10 15 20 25 IgG loading on PLGA microparticles (nM/OD550) DNA- Low DNA- Medium DNA- High T r a d i t i

• n

a l

Theoretical Footprint Limit

≅

ICEp can provide unique opportunities for boosting of immune cell efficacy

Co-stimulatory signals Cytokines Checkpoint inhibitors Adjuvants Antigens …

P

ICEp-𝛃-CD3/𝛃- CD28

T

CD3/CD28 Human primary T cells

CD4+ T CD8+ T

[1:5] [1:3] [1:1] [3:1] [5:1] 2×106 5.0×106 1.0×107 1.5×107 2.0×107 2.5×107 4×107 CD4+ T cell number at day 14

P = 0.0153

[1:5] [1:3] [1:1] [3:1] [5:1] 5×106 1×107 1.2×107 1.6×107 2.0×107 2.4×107 2.8×107 3.2×107 CD8+ T cell number at day 14

P = 0.0115

day 0 = 1.4x105

Local activation of AND-gate CAR-T cells by ICEp to enhance safety

P

CAR

TF

• 1. Roybal, et al. Cell, 2016
• 2. Huang, et al. BioRxiv, 2019

20 40 60 80 % Target killing by CD8+ T No ICEp Traditional chemistry GFP density

NSG mice dual tumor model for local CAR-T cell activation

4 8 12 16 600 1200 1800 2400

P = 0.5166 P = 0.6595 (n = 8) (n = 8)

Without ICEp With ICEp 4 8 12 16 600 1200 1800 2400

(n=6) P = 0.3092 P = 0.0075 P = 0.0032 (n=8) (n=8)

Tumor volume (mm3)

SynNotch CAR-T Untransduced T

Day after T cell injection

Huang, et al. BioRxiv, 2019

Acknowledgements

• Dr. Tejal Desai
• Dr. Ryan Chang

Zhongbo Li Desai lab members

• Dr. Wendell Lim
• Dr. Jasper Williams
• Dr. Wei Yu
• Dr. David Patterson

PBBR

Thank you!